Free-radical Bromination Scale-up

Let us, as a simple example, suggest useful modifications for the scale-up of the bromination of a heterocycle which has been previously performed in the laboratory with N-bromosuccinimide in carbon tetrachloride.  Since this is, superficially at least, a straightforward problem it can highlight the principles without overpowering us with the details.  Kilomentor will make the assumption from the reagent/solvent combination that this is a benzylic bromination of an alkyl substituent that is contemplated.

N-bromosuccinimide is not the most economical source of bromine atoms. 1,3-dibromo-5,5-dimethylhydantoin has a higher weight percentage of transferable bromine than other reagents(56%). This compares with 45% for NBS and 50% for liquid bromine wherein the latter only one half the bromine atoms get incorporated into the product. The cost of the hydantoin derivative per kilogram is also lower than for NBS . The Aldrich per kilogram prices are $109.60 and $135.00 respectively.

Unless there is a strong reason to the contrary, an optimization should use the least expensive reagent available at the expected scale.

To make the most realistic interpretations from the experimentation and to be able to make the soundest hypotheses to explain whatever we find, we should know whatever we can about the probable mechanism of the transformation. The benzylic bromination with NBS in carbon tetrachloride catalyzed by dibenzoylperoxide is a free radical catalyzed reaction. The reactions in the process are not all free radical however. The brominating agent is bromine radicals from molecular bromine not from the NBS itself.  NBS is just a reagent for converting each molecule of the co-product hydrogen bromide into one new molecular bromine and one succinimide. What is really happening is the free radical reaction of a low concentration of bromine with the aralkyl substrate.  

The development reactions should be done with shielding from laboratory lighting. When one scales up into a closed tank, there will no light entering the reaction vessel and so we do not want any photochemical reactions to complicate our study.

Dibenzoyl peroxide is most often the free radical initiator used in the literature; however it is not necessarily the best. Dibenzoyl peroxide decomposes into two types of radicals benzoic acid radicals and phenyl radicals produced from by decarboxylation from the former.

Azo initiators can also be used and have some advantages. According to William A. Pryor, Free Radicals. McGraw-Hill Inc. 1966:

“The most common azo initiator is azobis isobutyronitrile (AIBN). This useful initiator was first prepared in 1949 and has been widely used since. It has a half-life of 17 hours at 60 C and 1.3 hours at 80 C. This azo compound decomposes at the same temperature at almost the same rate in benzene,toluene, xylene, acetic acid, aniline, nitrobenzene, dodecylmercaptan, and isobutyl alcohol. This contrasts very markedly with benzoyl peroxide, for example, which has a rate of decomposition that is very solvent dependent. Furthermore, the rate of decomposition of AIBN in solvents such as toluene is essentially unaffected by inhibitors such as chloranil, iodine, or diphenylpicrylhydrazyl (DPPH). This implies that radicals do not attack the azo compound to produce an induced decomposition; if they did, the rate of disappeaance of the azo compound would be lower in the presence of substrates that would inhibit the radical chain decomposition. Induced decomposition is negligible for most azo compounds in solution; this sometimes makes them the preferred initiator for studies of radical reactions.” 

Furthermore, AIBN has worked where benzoyl peroxide has performed poorly. For example, see Fieser and Fieser, Vol. 1 pg. 45; H. Stockmann, J. Org., 29, 245 (1964).

We need a radical which will initiate a chain by removing a benzylic hydrogen. A benzylic radical is a nucleophilic radical so the faster reaction will be with an electrophilic initiator radical.  This is taught by Brian P. Roberts in his papers. A good review of this theory is in Polarity-reversal catalysis of hydrogen-atom abstraction reactions: Concepts and applications in organic chemistry, Chem. Soc. Rev.. 1999, 28, 25-35. The isobutyronitrile radical can be regarded as electrophilic since the alpha cyano carbanion would be a stabilized anion. This theory would predict that AIBN would be a better initiator than benzoyl peroxide. Advantageously, AIBN will be less sensitive to whatever changes in solvent we wish to implement.

Phenyl radicals from dibenzoyl peroxide could be regarded as electrophilic radicals since an sp² orbital can sustain a negative charge better than an ordinary sp³ orbital. Nevertheless, its electrophilicity cannot match an alpha cyano carbanion. The latter would be expected to react more quickly to generate the nucleophilic benzylic radical we need to achieve overall bromination.  If we still want to use dibenzoylperoxide as reagent a catalytic amount of trimethylamine thexylborane or triethylamine borane could act as catalyst by polarity reversal.